Delivery systems are often essential in safely administering active agents. Delivery systems can be used to optimize bioavailability, improve dosage consistency and improve patient compliance (e.g., by reducing dosing frequency). Solutions to drug delivery and/or bioavailability issues in pharmaceutical development include, for example, converting known active agents to prodrugs. Typically, in a prodrug, a polar functional group (e.g., a carboxylic acid, an amino group, phenol group, a sulfhydryl group, etc.) of the active agent is masked by a promoiety, which is labile under physiological conditions. Accordingly, prodrugs are usually transported through hydrophobic biological barriers such as membranes and may possess superior physicochemical properties in comparison to the parent drug. Prodrugs are preferably non-toxic and are preferably selectively cleaved at the locus of drug action. Ideally, cleavage of the promoiety occurs rapidly and quantitatively with the formation of non-toxic by-products (i.e., the hydrolyzed promoiety).
Many active agents, particularly those that are orally available, are susceptible to intentional abuse (e.g., narcotics, amphetamines and other controlled substances) or unintentional abuse (e.g., overdose by impaired or non-compliant patients or infants). Conventional methods such as micro-encapsulation and enteric coating technologies, although successful in delivering many active agents, have had limited success in reducing abuse of active agents such as narcotics, amphetamines, etc.
Accordingly what is needed are prodrugs of active agents, which in addition to potentially increasing bioavailability and having superior physiochemical properties, are also resistant to patient abuse.